The behavioral effects of cannabinoids are thought to be mediated through a brain (CEJ1) receptor, structure-activity relationships (SAR) for which have been developed. Ligands of diverse structural types have been prepared, some of which are much more potent than delta-9-THC, the psyohoactive constituent of marijuana. A second (CB2) receptor has been identified which is expressed in the mmune system and certain cancer cells. SAR for the CB2 receptor are not well defined; but ligands which show selectivity for it have been identified. The major goal of our program continues to be the exploration of structural similarities and dissimilarities among different classes of cannabinoids and the development of agonists and antagonists with selective pharmacological profiles. These goals will be reached through Ihe synthesis of new potential agonists and antagonists. Pharmacological evaluation of the ligands will be carried out through a collaborative agreement with Dr. B. R. Martin, Virginia Commonwealth University. Other pharmacological investigations will be performed by Dr. R. G. Pertwee, University of Aberdeen (UK). New ligands to be synthesized include indole pyrrole and pyridone based potential agonists and antagonists to obtain additional ligands with receptor selectivity, selective agonist properties and/or to provide additional insight into the manner in which cannabimimetic indoles and pyrroles interact with each receptor. Rigid indole analogues will be prepared and their pharmacology evaluated. Additional 1-deoxy- and 1 -methoxycannabinoids that are designed to be highly selective agonists for the CB2 receptor, with little affinity for the CB1 receptor will be prepared. These ligands should provide insight into the possibility of hydrogen bonding interactions of ligands with the CB2 receptor, and their pharmacology may provide additional insight into the biological role of the CB2 receptor. Several deoxy-THC derivatives with little affinity for the CB1 receptor exhibit in vivo cannabinoid activity Investigations into the origins of this activity will be carried out. Hydroxylated derivatives of H-hydroxy-delta-8-THC-DMH and CP 55,940 will be synthesized to explore the SAR of this series of compounds. There a possibility that these metabolites may be contributing to the enhanced potency of cannabinoids with a dimethylheptyl side chain.